IL-6 is a cytokine called B-cell stimulating factor 2 (BSF2) or interferon β2. IL-6 was discovered as a differentiation factor responsible for activation of B-lymphatic cells (Hirano, T. et al., Nature (1986) 324, 73-76). Thereafter, it was found to be a multifunctional cytokine that influences the function of various cells (Akira, S. et al., Adv. in Immunology (1993) 54, 1-78). IL-6 has been reported to induce the maturing of T lymphatic cells (Lotz, M. et al., J. Exp. Med. (1988) 167, 1253-1258).
IL-6 propagates its biological activity through two proteins on the cell. One of them is a ligand-binding protein with a molecular weight of about 80 kD to which IL-6 binds (Taga T. et al., J. Exp. Med. (1987) 166, 967-981; Yamasaki, K. et al., Science (1987) 241, 825-828). IL-6 receptor occurs not only in a membrane-bound form that penetrates and is expressed on the cell membrane but also as a soluble IL-6 receptor consisting mainly of the extracellular region.
The other is non-ligand-binding membrane-bound protein gp130 with a molecular weight of about 130 kD that takes part in signal transduction. IL-6 and IL-6 receptor form an IL-6/IL-6 receptor complex, to which gp130 is bound, and thereby the biological activity of IL-6 is propagated into the cell (Taga et al., Cell (1989) 58, 573-581).
IL-6 antagonists are substances that inhibit the transduction of IL-6 biological activities. Up to now, there have been known antibodies to IL-6 (anti-IL-6 antibodies), antibodies to IL-6 receptor (anti-IL-6 receptor antibodies), antibodies to gp130 (anti-gp130 antibodies), reshaped IL-6, IL-6 or IL-6 receptor partial peptides, and the like.
Antibodies to IL-6 receptor have been described in a number of reports (Novick D. et al., Hybridoma (1991) 10, 137-146; Huang, Y. W. et al., Hybridoma (1993) 12, 621-630; International Patent Application WO 95-09873; French Patent Application FR 2694767; U.S. Pat. No. 5216128). A humanized PM-1 antibody was obtained by implanting the complementarity determining region (CDR) of a mouse antibody PM-1 (Hirata et al., J. Immunology (1989), one of anti-IL-6 receptor antibodies, 143, 2900-2906) into a human antibody (International Patent Application WO 92-19759) has been known.
Generally psoriasis is a chronic and intractable dermatosis, and has an appearance in which white or silver white keratin has been formed on red-colored (erythema) circular or elliptic protrusions. Psoriasis is a typical dermatosis of erythrosquamatous dermatoses, and this erythrosquamatous dermatoses is a cutaneous symptom in which “inflammation” resulting from the invasion of leukocyts such as lymphocytes into the skin, and “karatosis” in which the epidermis and the horny layer of the skin become thick are simultaneously present.
Although psoriasis is divided into psoriasis vulgaris, psoriatic arthritis, pustular psoriasis, palmoplantar pustulosis, and psoriasis guttata by symptom, the etiology and the mechanism of onset have not been elucidated. However, the fact that cyclosporine having a lymphocyte-suppressing activity has a therapeutic effect on psoriasis led to the hypothesis that lymphocytes are involved.
Known therapeutic agents for psoriasis include steroids for external use, cyclosporine for internal use, methotrexate for internal use, UV therapy, etc. for controlling the inflammation of the skin; vitamin D for external use, retinoids (Tigason) for internal use, UV therapy, etc. for controlling the growth (keratosis) of the epidermis; nonsteroidal anti-inflammatory drugs (for arthritis of psoriatic arthritis), antibiotics (for related infections), etc. for treating other individual related conditions.
However, there have been no attempts so far to control specifically the biological activity of IL-6 using IL-6 antagonists such as anti-IL-6 receptor antibody in psoriasis, and it was not known that IL-6 antagonists such as anti-IL-6 receptor antibody exhibits a therapeutic effect for psoriasis.